The purpose of this TTURC proposal is to examine tobacco exposure reduction methods to treat smokers who have been resistant to conventional methods of intervention or who have not been previously targeted. Reduction of tobacco use will be examined both as a potential transitional goal toward cessation, or as an endpoint for refractory smokers. The center grant proposal involves five research projects and three cores. The five projects vary from animal studies to human clinical trials. Dr. Paul Pentel will use animal models of nicotine self- administration to study the use of high dose nicotine (doses producing plasma nicotine concentrations exceeding those experienced by smokers) as a treatment strategy. The combined use of high dose nicotine and the antagonist mecamylamine, and the effects of high dose nicotine on tobacco carcinogen activation will also be evaluated. Dr. Dorothy Hatsukami will conduct short-term, tightly-controlled human behavioral pharmacology studies that examine different methods of reducing toxic exposure to tobacco. These methods include nicotine replacement products and behavioral methods to reduce the amount of cigarettes smoked. Drs. Larry An, Harry Lando and Anne Joseph will examine exposure reduction treatment methods in targeted populations unable or unwilling to become abstinent or who are on the trajectory towards nicotine dependence. The targeted populations to be examined will vary across the life span including mothers who smoke, adolescent experimental smokers and medically compromised smokers. Research on each population will have unique as well as common methods for assessment and treatment with the primary outcome measures being the reduction in tobacco use and toxicity, the degree to which these treatments facilitate abstinence, and the cost- effectiveness of these approaches. The Core facilities will include Biomarker, Administrative, and Design and Analysis Cores. Drs. Stephen Hecht and Sharon Murphy will be co-directors of the Biomarker Core. This Core will provide measurement of biomarkers for tobacco, nicotine and carcinogen exposure and the capability to phenotype individuals according to their metabolism of nicotine. The Design and Analysis Core will be responsible for data input, monitoring and statistical analyses and for performing the economic and policy analyses for each of the clinical studies. The Administrative Core will be responsible for the smooth and coordinated operation of the studies, the training and career development of students and faculty, and the dissemination of information. In summary, the goal of this highly interdisciplinary center grant is to systematically examine tobacco exposure reduction methods that will decrease mortality and morbidity associated with tobacco use.